Biomedical subjects
Publications and source records attributed to T Thorsteinsson.
The effect of soft long chain quaternary ammonium antibacterial agents on the in vitro gene delivery of a luciferase plasmid to COS-1 cell lines was investigated. Low concentrations of these compounds could be used to enhance gene delivery with Lipofectamine Plus.
Environmental friendly antibacterial agents have to degrade relatively rapid to non-toxic and inactive products after they have had their desired effect. Environmental friendly quaternary ammonium agents were designed according to Bodor's soft drug approach and evaluated in vitro. Structure-activity relationship (SAR) studies showed that the antibacterial activity of a given soft agent will only be acceptable if its chemical stability is adequate to allow the agent to express its activity for sufficient duration of time. However, the studies also showed that increasing the lipophilicity of a chemically labile antibacterial agent could increase its potency. Two of the lipophilic quaternary ammonium antibacterial agents evaluated had minimum inhibitory concentration (MIC) against Staphylococcus aureus as low as 2 microg/ml and estimated degradation half-life less than 4 to 6 days at room temperature. Decreased MIC could only be obtained by increasing the degradation half-life of the agents.
Hard drugs have been defined as drugs that are biologically active and non-metabolizable in vivo. Soft drugs are defined as drugs, which are characterized by predictable and controllable in vivo destruction (i.e. metabolism) to form non-toxic products after they have achieved their therapeutic role. Quaternary ammonium compounds, such as benzalkonium chloride, are hard antibacterial agents. Their toxicity limits their usage in humans and animals, and their chemical stability limits their usage for general environmental sanitation. Furthermore, due to their stability they are prone to induce selective antimicrobial pressure and bacterial resistance. Soft analogs of the currently available hard antibacterial agents are less toxic. However, although the soft analogs have been shown to possess antibacterial activity in in vitro studies, it is likely that their in vivo activity will be hampered by their chemical instability.
ETH-615 is an amphoteric drug that forms a water-insoluble zwitterion at intermediate pH values. Increasing the aqueous solubility of ETH-615 through cyclodextrin complexation did not enhance transdermal delivery of the drug from saturated aqueous solutions. However, increasing the lipophilicity of the drug through masking of the anionic group with a pro-moiety increased the dermal and transdermal delivery of the drug. Furthermore, masking the anionic group enhanced the chemical stability of the drug, resulting in significant improvement of the shelf life of the drug in both aqueous and nonaqueous solutions.
Previously we have shown that the diacyl glyceryl ester of naproxen is absorbed into excised mouse skin and slowly degraded to release naproxen. In the present work we have synthesised some organic acid and fatty acid derivatives of metronidazole, and studied the in-vitro degradation in aqueous buffer solutions and serum as well as their permeation through hairless mouse skin. The derivatives were enzymatically degraded in serum to form metronidazole. Only the acetic acid and butyric acid derivatives were able to permeate hairless mouse skin intact. The fatty acid derivatives released metronidazole within the skin. The metronidazole delivery through the skin was significant when the metronidazole oleate was used. This compound could therefore be considered as a suitable pro drug for dermal applications.
Diacyl glyceryl ester derivatives of naproxen were synthesized and tested for transdermal and dermal administration. Diacyl derivatives of aliphatic acids of various chain length were compared. The pharmaceutical properties of these compounds, such as lipophilicity, hydrolysis in a buffer solution at various pH values and degradation in human serum and hairless mouse skin homogenate, were investigated. All the diacyl derivatives were relatively stable in a neutral buffer solution, but were rapidly degraded to release naproxen in human serum and hairless mouse skin homogenate. The diacyl compounds could not penetrate hairless mouse skin in vitro. However, significant absorption into the skin could be measured, and this increased with increasing lipophilicity. A more than 100-fold difference in absorption was observed. The prodrugs were slowly hydrolyzed to naproxen inside the skin. The release of naproxen to the receptor compartment of diffusion cells showed that this type of prodrug could be used for controlled drug delivery.
17 beta-Estradiol is almost insoluble in water. The effect of various cyclodextrins and two different polymers, polyvinylpyrrolidone (PVP) and carboxymethylcellulose (CMC), on the aqueous solubility of 17 beta-estradiol was investigated. 17 beta-Estradiol was dissolved in aqueous 50% w/v 2-hydroxypropyl-beta- cyclodextrin (HP beta CD) solution containing 0.25% (w/v) CMC and the dry 17 beta-estradiol-HP beta CD complex formed by lyophilisation of the solution. Sublingual tablets from the dry complex were produced by direct compression. The dissolution of 17 beta-estradiol from tablets containing the drug in a lyophilised HP beta CD complex was determined. For reference the dissolution of 17 beta-estradiol was determined from tablets containing physical mixture of 17 beta-estradiol and HP beta CD or tablets containing 17 beta-estradiol without HP beta CD. Sublingual tablets containing 17 beta-estradiol-HP beta CD in the lyophilised complex demonstrated the fastest dissolution profile and those tablets were selected for further studies in humans. Six postmenopausal women received a sublingual tablet containing 17 beta-estradiol-HP beta CD complex equivalent to 100 micrograms 17 beta-estradiol. Blood samples were collected over a 12 h period and the 17 beta-estradiol plasma concentration was determined. 17 beta-Estradiol was rapidly absorbed from the sublingual tablets, resulting in a peak 17 beta-estradiol plasma concentration of 568 +/- 97 pmol/l 15 min after administration of the tablets, followed by a biphasic elimination.
OBJECTIVE: To monitor trends in mortality and morbidity due to ischaemic heart disease and compare these with observed levels of risk factors from population surveys. DESIGN: Analysis of trends in death rates from ischaemic heart disease in Iceland compared with expected rates computed from population surveys. Risk factor levels together with beta factors obtained from Cox's regression analysis were used to compute expected death rates. Trends in morbidity due to acute myocardial infarction were assessed and secular trends in dietary consumption compared with trends in cholesterol concentrations. SETTING: Reykjavik, Iceland (total population 250,000; over half the population live in Reykjavik). SUBJECTS: 12,814 randomly selected residents in the Reykjavik area aged 45-64 (6623 men, 6191 women; 72% and 80% of those invited). MAIN OUTCOME MEASURES: Age adjusted rates of myocardial infarction and deaths from ischaemic heart disease. Expected risk from risk factor levels (smoking, total serum cholesterol concentration, systolic blood pressure) at each unique survey visit. RESULTS: Mortality from ischaemic heart disease has decreased by 17-18% since 1970. During 1981-6 the myocardial infarction attack rate in men under 75 decreased by 23%. A decrease occurred in the level of all three major risk factors after 1968. The fall in the serum cholesterol concentration coincided with a reduction in consumption of dairy fat and margarine. The calculated reduction in risk for the age group 45-64 was about 35%, which was closely similar to the observed decrease in mortality due to ischaemic heart disease in that age group. CONCLUSION: The reduction in mortality from ischaemic heart disease was substantially due to a decreased incidence of myocardial infarction and could be attributed largely to the reduction in risk factors.
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A case is reported, where the median nerve was entrapped in a supracondylar humerus fracture, not preventing closed reduction. As serious impairment of the median nerve function did not improve within ten weeks, the nerve was explored and dissected out of the humerus using microsurgical technique, leading to complete recovery of the neural function. The purpose of this report is to draw attention to the fact, that the median nerve can be enclosed in supracondylar fractures reducable to good position and further, that delicate dissection of the nerve out of the bone does not necessitate sacrifice of its continuity.
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Four patients, all children, with dislocation and entrapment of the median nerve and brachial artery following supracondylar fractures of the humerus are described. Circulation and neural function were restored in all cases by operation. Exploration of the neurovascular structures is recommended if dislocation and entrapment of the median nerve and brachial artery are suspected.
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In the first stage of a prospective cardiovascular health survey, 2955 males aged 34-61 years were invited for examination during a 12-month period. The response was 75%. Appointments were arranged in such a way that all age groups would be equivalent with respect to time of day, weekday and time of year on which appointments were given. In fasting blood and urine samples the following quantities were estimated: s-alkaline phosphatase (AP), s-bilirubin (Bil), s-creatinine (Cre), s-uric acid (UA), haemoglobin (Hb), haematocrit (Hct), mean cell haemoglobin content (MCHC), erythrocyte sedimentation rate (ESR) and urine specific gravity (USG). The approximate 5% and 95% centiles were as follows: (table; see text) No indication of seasonal variation was found in these results.
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The participants in a community health survey in the Reykjavik area answered the question whether a first-degree relative had had myocardial infarction (MI), hypertension (HT) or cerebral stroke. The mean total serum cholesterol level was 5-10 mg/dl higher in the group with a positive history of MI than in the negative group. The frequency of hyperlipidaemia and the levels of other risk factors measured (blood pressure and body mass index) were similar in both groups. The group with a positive family history (FH) of HT had a mean systolic blood pressure 6-8 mmHg higher and diastolic hypertension (greater than 105 mmHg) on a single measurement twice as frequently as the negative group. The mean systolic blood pressure in the group with positive FH of stroke was 8-10 mmHg higher than in the negative group. The study thus suggests that positive FH of HT or stroke among first-degree relatives is a worthy indication for blood pressure measurements, at least after the age of 40.
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